David W.C. Yeung

Radiolabeled MDA2, an oxidation-specific, monoclonal antibody, identifies native atherosclerotic lesions in vivo

BackgroundOxidatively modified low-density lipoprotein (LDL) is present in atherosclerotic but not normal arteries and plays a crucial role in the pathogenesis and adverse consequences of atherosclerotic lesions. We previously generated a series of monoclonal antibodies (MoAb) against oxidation-specific neo-epitopes formed during the oxidative modification of LDL. MDA2, a prototype MoAb, recognizes malondialdehyde-lysine epitopes (eg, in malondialdehyde-modified LDL) within atherosclerotic lesions. We describe the in vivo characteristics of MDA2 and initial noninvasive imaging studies of atherosclerosis in rabbits.MethodsTo assess the in vivo specificity of MDA2 for atherosclerotic lesions, iodine 125-MDA2 was intravenously injected into 7 LDL-receptor deficient Watanabe heritable hyperlipidemic (WHHL) and 2 normal New Zealand white (NZW) rabbits, and the aortic plaque uptake was evaluated 24 hours later. 125I-Halb, an isotype-matched irrelevant MoAb that binds to human albumin, was injected into 5 WHHL and 2 NZW rabbits as a control. Aortic autoradiography was performed, and the mean uptake of MoAbs was measured as the percent injected dose per gram aortic tissue. Gamma camera imaging was then carried out in 7 WHHL rabbits and 2 NZW rabbits with 99mTc-MDA2. Imaging was carried out at 10 minutes and at 12 or 24 hours. Malondialdehyde-LDL was then injected to clear the blood pool signal, and final images were obtained 2 hours later.ResultsMean uptake of 125I-MDA2 in the entire aorta was 17.4-fold higher in WHHL than in NZW aortas (P<.001), and 2.8-fold higher than 125I-Halb in WHHL aortas. 125I-MDA2 also had higher specificity for lesioned areas than 125I-Halb (plaque/normal ratio 6.3 vs 2.9, P<.001). Autoradiograph of aortas of 125I-MDA2-injected WHHL rabbits revealed uptake in lipid-stained lesions with absence of signal in adjacent normal arterial tissue. Immunostaining of WHHL lesions, which accumulated MDA2 as noted on autoradiography, revealed that uptake was highest in areas with abundant foam cells and in lipid-rich necrotic core areas. Autoradiograph of aortas from NZW rabbits injected with 125I-MDA2 did not yield any visible signal. Planar gamma camera in vivo scintigraphy revealed a visible signal in 4/7 WHHL rabbits, which was confirmed by aortic Sudan staining.ConclusionRadiolabeled MDA2 shows excellent in vivo uptake and specificity for atherosclerotic lesions containing abundant oxidation-specific epitopes. The in vivo imaging studies suggest that noninvasive imaging of oxidation-rich atherosclerotic lesions with radiolabeled MDA2 may be feasible in human beings with optimization of the imaging methods.

Dual-Tracer PET/CT Imaging in Evaluation of Metastatic Hepatocellular Carcinoma

We have reported previously that 11C-acetate (11C-ACT) PET was complementary to 18F-FDG PET in the evaluation of primary hepatocellular carcinoma (HCC) in relation to the degree of tumor cellular differentiation. In this retrospective study, our goals were to further explore the complementary role of 11C-ACT and 18F-FDG PET in the detection of metastatic HCC disease, to evaluate the tracer characteristics of individual organ metastasis, to identify the risk factors of metastasis, and to evaluate how these results could affect patient management. Methods: One hundred twenty-one patients were selected for this study. All patients had undergone a “dual-tracer” PET/CT same-day protocol with 11C-ACT PET/CT followed by 18F-FDG PET/CT. Sets of criteria were chosen to define “metastasis” and “no metastasis” on a patient basis. The patients considered as true-positive (n = 97) were then divided into 4 groups on the basis of their primary HCC tracer avidity: 18F-FDG-avid group, 11C-ACT-avid group, 18F-FDG- and 11C-ACT-avid group, and a posttreatment group with metastasis but no baseline dual-tracer PET characterization of the primary tumor and no hepatic recurrence. Results: On a patient basis, dual-tracer PET/CT had a sensitivity of 98%, a specificity of 86%, a positive predictive value of 97%, a negative predictive value of 90%, and an accuracy of 96% in the detection of HCC metastasis. On a lesion basis, 273 metastatic HCC lesions considered as true-positive were detected and categorized according to the organ or site of metastasis: lymph node (abdominal and thoracic, 49%), lung (32%), bone (8%), and others (10%). The lesion-based and patient-based detection sensitivities were 60% and 64%, respectively, by 11C-ACT and 77% and 79%, respectively, by 18F-FDG, and they were complementary. In analyzing lesion tracer avidity, there was a positive statistical correlation between primary HCC avidity with the general tendency of metastasis. Clinically significant changes in management were found in patients with true-positive metastasis, of whom 19% were affected by 11C-ACT PET alone. Dual-tracer PET/CT was more effective than single-tracer PET/CT in identifying candidates for curative therapy (negative predictive value of dual-tracer, 18F-FDG, and 11C-ACT PET/CT: 90%, 49%, and 37%, respectively). Conclusion: This study confirmed that 18F-FDG PET/CT is useful in the evaluation of HCC metastasis, although its role in the diagnosis of primary HCC is more limited. Dual-tracer PET/CT had an incremental value and complementary advantage when compared with single-tracer imaging in the evaluation of HCC metastasis.

Phase I Trial of Adoptive Immunotherapy With Cytolytic T Lymphocytes Immunized Against a Tyrosinase Epitope

PURPOSE To study distribution and toxicity of cytolytic T lymphocytes (CTLs) against a single melanoma epitope. PATIENTS AND METHODS CD8(+) T cells obtained by leukapheresis from 10 patients with disseminated HLA-A2.1(+), tyrosinase-positive melanomas were immunized in vitro against tyrosinase(369-377) (YMNGTMSQV). Drosophila cells transduced with HLA-A2.1, CD80, and CD54 (intracellular adhesion molecule-1) were used for priming, followed by two rounds of immunization with mononuclear cells as antigen-presenting cells. 1 x 10(8) CTL were infused intravenously (IV) on day 1. CTL frequency was measured by limiting dilutions in five patients. (111)In labeling and scintigraphy measured distribution of CTL in next five. Five days later, 1 x 10(8) CTLs were infused on 4 successive days to both groups. Immunohistology of response was judged by biopsies. RESULTS Infusions were nontoxic. CTLs were undetectable in the blood, going to lungs within 5 minutes. At 4, 24, and 72 hours, they were found in liver and spleen. Lesions were visualized by scintiscans in one responding patient where two subcutaneous nodules were noted at 4 and 24 hours. A second patient had a partial response and remains alive with disease 2 years later. CD8(+) T cells were found in lesions of responders, associated with the presence of HLA-A2 molecules and tyrosinase. Two nonresponders without tyrosinase and HLA-A2 molecules had a paucity of CD8(+) T cells in their lesions. Whether the CD8(+) T cells in lesions of responders were those we had reinfused is uncertain. CONCLUSION CTLs immunized against a single melanoma epitope were nontoxic but did not specifically localize to tumor sites. Nevertheless, two patients had disease regression. Additional therapeutic studies with specifically immunized CTL seem justified.

Nasopharyngeal carcinoma: relationship between 18F-FDG PET-CT maximum standardized uptake value, metabolic tumour volume and total lesion glycolysis and TNM classification.

PurposeWe aimed to evaluate the relationships between primary tumour; maximum standardized uptake value (SUVmax), metabolic tumour volume (TV) and total lesion glycolysis (TLG) and tumour-node metastases (TNM) classification in nasopharyngeal carcinoma (NPC) patients. MethodsFluorine-18 fluorodeoxyglucose positron emission tomography-computed tomography scans of 57 consecutive newly diagnosed NPC patients (age range, 15–80 years) were retrospectively reviewed. SUVmax, TV and TLG were recorded. Two-tailed Spearmans correlation was used to analyse the relationships between the metabolic parameters and the TNM staging system. ResultsPositive correlations were observed between SUVmax (P<0.001, R=0.516), TV (P<0.001, R=0.504) and TLG (P<0.001, R=0.620) and T-stage, and both TV and SUVmax were independent variables that significantly affected T-stage (P<0.001, adjusted R2=0.370). No other significant correlations were found between the metabolic parameters and TNM classification system. ConclusionThe metabolic parameters derived from fluorine-18 fluorodeoxyglucose positron emission tomography-computed tomography were positively correlated with T-stage in primary NPC. Our findings may suggest a complementary role of these parameters to TNM staging in prognostication of NPC patients.

Reduction in cortical IMP-SPET tracer uptake with recent cigarette consumption in a young group of healthy males

Functional brain imaging techniques are being used increasingly to infer disturbances in brain function in various neuropsychiatric disorders, but the specificity of such findings is not always clear. We retrospectively examined the effects of one possible confound - cigarette smoking - on cortical uptake of iodine-123 iodo-amphetamine (IMP) using single-photon emission tomographic imaging in a young (mean age=35 years) healthy group of male controls divided according to their smoking history. Subjects who had never smoked (n=17), or those with a history of smoking but no recent smoking (n=8), had equivalent and significantly higher mean cortical uptake of IMP than subjects with a history of smoking and who were current smokers (n=8). There were no differences in the cortical distribution of IMP. Our results indicate that cigarette smoking has an acute effect on global cerebral blood flow. This potential confound must be considered before abnormalities in cortical tracer uptake are attributed to some neuropsychiatric disorder of interest.

Pilot Study of Positron Emission Tomography (PET) Brain Glucose Metabolism to Assess the Efficacy of Tongue and Body Acupuncture in Cerebral Palsy

We aimed to assess the efficacy of tongue and body acupuncture with clinical function and brain glucose metabolism in children with a severe type of cerebral palsy. Four children were recruited. The motor function belonged to grade 5 of the Gross Motor Function Measure (ie, completely nonambulatory). Daily tongue and body acupuncture was applied for 5 days a week for 8 weeks. The Functional Independence Scale for Children (WeeFIM), Clinical Global Impression Scale (CGIS), and positron emission tomography of the brain with [18F]fluorodeoxyglucose (FDG) were performed at baseline and after acupuncture. None of the children had any significant change in the Functional Independence Scale for Children score, despite the fact that all mothers scored 3 on the Clinical Global Impression Scale (ie, 25% improvement) in overall function. The brain glucose metabolism, however, showed a > 10% increase in the frontal, parietal, temporal, and occipital cortices and cerebellum. Thus, a short course of tongue and body acupuncture was shown to increase brain glucose metabolism, despite lacking any clinical functional improvement seen within the 8-week course, possibly owing to the severity of the motor dysfunction and the short duration of treatment. The objective increase in brain glucose metabolism might serve as a surrogate marker for assessing the subclinical efficacy of an alternative treatment before any objective clinical improvement is evident. A larger-scale study for different degrees of severity of cerebral palsy and an impairment model should be undertaken to correlate clinical with neurometabolic change. ( J Child Neurol 2006;21:455—462;

Prognostic Impact of Standardized Uptake Value of F-18 Fdg Pet/ct in Nasopharyngeal Carcinoma

Purpose: We evaluated the use of metabolic parameters of F-18 fluorodeoxyglucose positron emission tomography (FDG PET) for the assessment of the primary tumor and nodal metastasis in predicting survival in nasopharyngeal carcinoma (NPC) patients. Materials and Methods: The F-18 FDG PET/CT (computed tomography) scans of 46 consecutive newly diagnosed NPC patients were retrospectively reviewed. Maximal standardized uptake value (SUVmax) corrected for lean body mass of primary tumor (pSUVmax) and highest SUVmax of cervical lymph nodes (nSUVmax) were recorded. The association of FDG uptake and 2-year disease-free survival (DFS) was examined. Results: Significantly better DFS was found in patients with pSUVmax <7.5 and nSUVmax <6.5 (P = 0.042 and P = 0.019, respectively). In multivariate analysis, both pSUVmax and nSUVmax were significant independent predictors of DFS. Conclusions: The SUVmax of the primary tumor and nodal metastasis are useful parameters for predicting DFS in NPC patients.

Hypocalcemic Heart Failure in End-Stage Renal Disease

A 37-year-old woman presented with hypocalcemic heart failure complicating end-stage renal disease. Heart failure persisted despite conventional therapy but improved after correction of hypocalcemia. Continuous monitoring of left ventricular function by radionuclide study during calcium replacement showed dramatic improvement. Our case showed that hypocalcemia could be a rare but reversible cause of frank heart failure in uremic patients.

Pilot study of efficacy of tongue and body acupuncture in children with visual impairment

We studied the efficacy of tongue and body acupuncture in affecting visual recovery in children with central and peripheral visual disorders. Twelve children (five boys, seven girls) (age range 18 months to 14.5 years) with visual disorder with static functional visual ability for at least 12 months were recruited for the study. The causes of cortical visual impairment (10) included severe perinatal asphyxia (4), postencephalitis (1), traumatic brain injury (1), hydrocephalus (1), and increased intracranial pressure (3). Peripheral causes (2) were due to congenital optic atrophy. We used the following assessment tools: clinical visual improvement, defined as improvement of vision by one grade in one or both eyes with measurement of visual acuity; the functional visual outcome scale of 0 to 5, with positive outcome defined as improvement in one level on a functional scale; visual evoked potential, with positive improvement defined as 10% improvement in P100 latency of one or both eyes; [18 F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) of the brain, with positive improvement defined as a 10% increase in glucose metabolism in one or both occipital lobes; and the Clinical Global Impression Scale (parental report). Tongue and body acupuncture consisted of 60 sessions, with 5 sessions per week. Four children showed clinical or functional improvement (33%). Of nine children with abnormal visual evoked potentials, five had improvement (56%). Of seven children who underwent PET, six had improvement in glucose metabolism in the visual cortex (86%). Seven parents (58%) reported improvement (three children had 75% improvement; four children had 25% improvement). There was a significant correlation between the interval of onset of visual impairment and starting treatment with clinical or functional outcome, with a longer interval resulting in a better outcome (P = .0282). However, there was no correlation between cause, severity, or clinical or functional visual outcome with improvement in the visual evoked potential or PET. We demonstrated that tongue and body acupuncture can improve the visual status of children with visual disorders, both peripheral and central in origin. As children with chronic visual impairment also showed some visual recovery, more studies should be done to assess the full potential of acupuncture as an adjunct to Western medicine in neuroplasticity. (J Child Neurol 2006;21:462—473;

Is there a relationship between delta sleep at night and afternoon cerebral blood flow, assessed by HMPAO-SPECT in depressed patients and normal control subjects? Preliminary data.

We wished to explore the relationships between waking HMPAO uptake and visually scored polysomnography. We hypothesized that HMPAO activity would correlate positively with slow wave sleep measures the same night. Eight unmedicated unipolar patients with current DSM-IV major depression (17-item Hamilton Depression Rating Scale score 21.5+/-2.9) and seven control subjects received polysomnography on 2 consecutive nights. On the afternoon following the adaptation night, subjects received cerebral SPECT, with 15 mCi Tc-99m-HMPAO injected while subjects performed the Continuous Performance Task. Patients and control subjects did not significantly differ on demographic, polysomnographic, and SPECT variables. Slow wave sleep measures correlated positively (Spearmans) with global and regional tracer activity for depressed (n = 8), control (n = 7) and combined groups (n = 15); in other words, the greater the global or regional afternoon HMPAO uptake, the greater the slow wave sleep measures were the same night. In addition, the greater the waking afternoon global or regional HMPAO activity, the faster subjects fell asleep and the less Stage 2% they had. In patients, global and regional HMPAO activity correlated positively with REM density. Positive correlations between waking tracer activity and subsequent slow wave measures are consistent with previous hypotheses linking slow wave sleep with brain energy conservation and restoration. Further study is needed to determine whether these functional relationships differ in depression.